This invention relates to method and apparatus for measuring a property such as mass, size or density of target particles, and more particularly to such a method using a suspended microchannel resonator.
Precision measurements of nanometer- and micrometer-scale particles have wide application in pharmaceuticals/drug delivery, paints and coatings, foods, and other major industries and fields of research. This need is growing due to the expanding use of particulate engineering across these industries, to emerging nano- and micro-particle manufacturing techniques, and to recent regulations governing quality control in the pharmaceutical industry.
The most widely used particle-sizing technology is light scattering [Jillavenkatesa, 2001]. The names in brackets refer to the attached references, the contents of which are incorporated herein by reference. Light scattering is a mature technology that uses laser light passed onto or through a sample containing the target particles. In one form of light scattering known as laser diffraction, a spatial intensity pattern of the light diffracted by the particles is recorded. In another form, known as dynamic light scattering, the time dependence of scattered light intensity is recorded. The distribution of particle sizes is then inferred using various theoretical models of light diffraction or particle movement due to Brownian motion. Light scattering can be used to characterize particles whose sizes range from several hundred microns down to 1 nanometer or even below. In the majority of applications, particles are suspended in a fluid that carries them through the instrument. Light scattering is employed in a wide range of commercially available instruments from Beckman-Coulter, Malvern, Horiba, Shimadzu, and many other manufacturers.
Light scattering suffers from certain limitations. For example, when using laser diffraction, determining particle size accurately can be problematic for some applications due to subtleties in the light scattering models. For a wide class of particles, a priori knowledge of the optical indices of refraction of the particles and the carrying medium is required, and errors in the index values result in errors in estimated size [Keck 2000, Jillavenkatesa 2001]. For example, many paint pigments are made up of particles whose optical properties and shape affect their bulk color, and index parameters must be measured prior to size measurement [Ley]. Other examples include artifacts introduced by irregularly shaped particles that can cause errors when attempting to determine the particle volume and the “equivalent” spherical radius. Laser diffraction is also known to be problematic when measuring widely polydisperse and multimodal samples, for which measurements may miss entire peaks in the distribution of particle sizes, or indicate spurious peaks in the size distribution [Keck 2000, Driscoll 2001]. In the case of dynamic light scattering (DLS, also referred to as photon-photon correlation), the instruments detect a laser speckle pattern in the diffracted light, and monitor the pattern's changes in time that are caused by the Brownian motion of the particles. The autocorrelation function of the time dependence of this intensity is interpreted with the help of a theoretical model to infer the particle sizes. The resolution of DLS, i.e., its ability to distinguish among particles closely spaced in size, is fairly low, and this method is not well suited to providing the details of a complex distribution of particle sizes.
In order to reduce error and to increase resolution, when measuring polydisperse samples with light scattering, the samples are often “fractionated”, i.e., the particles are sorted according to size, prior to measurement by light scattering. The sub-samples of different size “bins” are then measured successively with the light scattering instrument, and the overall distribution is built up. A number of fractionation techniques can be employed (settling, centrifuge, asymmetric field flow). The added sample preparation, the need to run several sub-samples, and additional equipment all add time and expense to the overall measurement.
In the case of laser diffraction, obtaining high resolution and wide dynamic range in the size measurement requires a large number of detectors to capture light scattered at various angles. For example, one high-end light scattering instrument uses 126 detectors (Beckman Coulter LS 230 Laser Diffraction Particle Size Analyzer). Other instruments use multiple laser light sources and polarizing optics (Beckman Coulter LS 13 320 Multi-Wavelength Particle Size Analyzer). The refined optics needed in these instruments results in high cost, with some instrument prices greater than $50,000. And, these optics must be precisely aligned and carefully calibrated.
Light scattering instruments require a large number of particles in the laser beam to create good statistics for the measurement, and typically use a relatively large amount of target sample (typically several milliliters of high-concentration particles for the case of fluid suspension). This can be a burden for applications where the target material is expensive, rare, or difficult to handle. In addition, light scattering is limited to providing a measure of particle size. In many applications, it would be desirable to measure other particle properties, such as mass and density, that cannot be determined with optical methods.
Other techniques are also used for particle size analysis, each having their own tradeoffs and limitations [Jillavenkatesa 2001].
Measurement of particulate properties is important for organic targets such as cells and bacteria. The Coulter counter, which uses an electrozone measurement principle, is a standard technique for measuring cell volume. The resolution of this approach is typically limited to sizes above a micron. Measurements of cell mass and density have been correlated with disease and other physiological states, for example, in the case of malaria [Kramer 1982], but the measurement techniques for these quantities remain laborious. In sum, there is a significant need for improved methods of measuring particulate characteristics including size, mass, volume, and density, at high resolution, precision, and accuracy, for both inorganic and organic targets.